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Those who can eat as much as they please without gaining avoirdupois may feel smug about a paper in today’s Science, which reports that mice that lack insulin receptors only in their fat tissue outlive their normal brethren by about 18 percent. The paper, by Matthias Blueher, Ronald Kahn, and colleagues at the Joslin Diabetes Center in Boston, Massachusetts, is not directly related to Alzheimer’s, or even neurodegeneration and aging. But it touches sufficiently many threads across these fields to provoke thought by those interested in neurodegeneration and aging. For one, both fat intake and age-related type II diabetes have been linked to AD risk.

The Kahns have made their name in obesity and diabetes research. Here they asked whether caloric restriction, which has long been known to prolong life in different organisms, did so by reducing the metabolic rate associated with digesting food or did so as a consequence of leanness. Speaking for the former, mitochondrial respiration generates reactive oxygen species (ROS), which are widely thought to accelerate aging and are also implicated in Alzheimer’s disease through a variety of pathways including DNA damage, sensitivity to Aβ toxicity, and apoptosis. Speaking for the latter, age-related dysregulation of these complex pathways have also been implicated with longevity and with Alzheimer’s. For example, some researcher are finding that fat intake and age-related obesity increase the risk of developing AD, especially in ApoE4 carriers (see ARF related news story), but see also (see ARF related news story); see Peila et al.).

Insulin and insulin-related signal transduction pathways occur not only in fat but also in liver and muscle. To tease out the role of insulin in fat, Blueher et al. created knockout mice that lack only the fat-specific insulin receptor. These mice developed normally, but had 50 to 70 percent less fat than their normal littermates. Last July, Blueher had reported that these lean mice eat normally-even a tad more relative to body weight than the controls-yet remain free of the age-related obesity and ensuing glucose intolerance and insulin resistance that besets normal lab mice (Blueher et al, 2002) Now, it turns out that the thin mice also hung on to life in the mouse house more tenaciously. At 30 months, only half of the wildtype mice, but 80 percent of the knockouts, were still chowing down, and a quarter of them lived at 36 months when the wildtype mice had all died.

How so? The authors note that fruit flies and roundworms live longer if their mitochondrial respiration is repressed (e.g., Rogina et al., 2000, but see Steve Helfand’s comment below.) At the same time, both flies and worms also have been used to show that reducing insulin signaling increases lifespan (e.g., Kenyon et al., 1993). Of course, the insulin signaling connection is not nearly so simple, as overall insulin resistance is clearly pathologic (causing dwarfism when severe and diabetes when subtle) and shortens life span in mice and humans. This paper suggests that a key to this puzzle might lie in tissue selectivity in such a way that continued normal insulin signaling in muscle and liver, but reduced insulin signaling in fat are the most beneficial, and this is where caloric restriction may act through leanness.—Gabrielle Strobel

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Having been a neurologist in a former life, I have always wondered about how much aging plays a role in the neurodegenerative disorders. For some time it seemed that the debate (for it was a debate with little real information) fell into two categories. One point of view was that neurodegeneration is a disease and not a part of the normal aging process. The other viewpoint held that while it is a disease, it is age-related, so that the process of aging will impinge upon the timing and severity of the disorder. Some would go further to say that if people lived long enough, they would develop the neurodegenerative disorder, too. I think that these distinctions are less clear now. There certainly are a number of genetic and environmental factors that impinge upon the functioning and maintenance of the nervous system.

With regards to the Blueher et al. article, I think it is reasonable to assume that the aging process does impact strongly on neurodegenerative diseases, and interventions that either delay or slow down the aging process, or lead to a more healthy state, will either reduce or ameliorate many of the neurodegenerative disorders.

With regard to our work, the statement Bluher et al. make [about mitochondrial rate reduction extending life] we now know to be somewhat incorrect. Indy (for I’m not dead yet) long-lived flies have normal metabolic rates. At the time we published the Indy paper (Rogina et al., 2000), we did not know how a reduction in INDY led to life span extension. It was reasonable for Bluher et al. to think that the INDY protein is related to the mitochondria and would lead to a reduction in metabolism. However, we now know this not to be the case. The life-extending INDY protein is found on the plasma membrane, not the mitochondria (published last October, see Knauf et al, 2002), and in a paper in PNAS (see Marden et al., 2003), we show that the metabolic rate and physical activity of Indy long-lived flies is normal.

Regarding the question of whether metabolism and ROS reduction mediate the beneficial effect of caloric restriction, for me the issue is how does caloric restriction really lead to life span extension? There are clearly many different effects seen in a calorically restricted animal. Which ones are relevant to life span extension and which are associated with the restricted calorie state, but do not contribute to the life span change? One way of looking at the Bluher et al. paper is that an effect on fat tissue may be a direct downstream part of the pathway from caloric restriction to life span extension. For me, since no one knows the pathway or mechanism by which caloric restriction causes life span extension, there is a lot of room for speculation.

The analyses of mice with adipose cell-specific knockout of the insulin receptor (FIRKO mice) by Bluher et al. provide at least three major advances in our understanding the mechanisms whereby insulin signaling and energy metabolism regulate life span. First, they show that the life span of mice with impaired adipose insulin signaling is increased without a decrease in calorie intake. This result seemingly shatters the hypothesis that caloric restriction extends life span simply by reducing mitochondrial metabolism and oxyradical production. Second, their findings suggest that insulin signaling in different cell types may have different effects on overall energy metabolism and life span. These findings are intriguing and support possibly related findings of Wolkow et al., 2000, who showed that insulin signaling in the nervous system regulates life span in C. elegans. It remains unclear how insulin signaling in adipose cells reduces life span, but this is certainly an important area for further investigation. One possibility is stimulation by insulin of the release of hormones, lipids or other molecules that have a pro-aging effect.

Third, their data help to clarify an apparent contradiction between previous studies of insulin signaling and life span regulation in nematodes and rodents. Studies of C. elegans had shown that insulin signaling reduces life span, whereas increased insulin sensitivity (on a body-wide basis) is associated with increased life span in mammals. Caloric restriction, which extends life span, enhances insulin sensitivity in skeletal muscle while reducing fat mass. A generally similar increase in insulin sensitivity of nonadipose cells appears to occur in the FIRKO mice, although this needs to be examined in considerable detail. The initial phenotypes of FIRKO mice described in the study of Bluher et al. are remarkable, and suggest that these mice will provide a much-needed novel animal model for studies of mechanisms of aging and age-related disease.

Abandon your diets! Kahn and colleagues have examined the impact of selective loss of insulin receptors in adipose tissue on longevity in FIRKO (fat-specific insulin receptor knockout) mice. Disruption of insulin signaling appears not to be associated with diabetes or glucose intolerance. In addition, such mice have reduced fat mass, eat normally, and do not develop age-related obesity, which results in an overall extended mean life span.

In the nematode and the fruit fly, decreased insulin-like signaling also appears to extend life span. Conversely, in mammals and humans, severe disruption of the insulin receptor leads to insulin resistance associated with diabetes and obesity, which extrapolates to a shortened life span. The FIRKO mouse exhibits loss of insulin signaling in fat tissue only. Together with normal food intake and reduced overall adiposity, the authors propose the FIRKO mouse as an in vivo model for mimicking caloric restriction. Although not investigated, the reduction in fat mass is likely due to an increased metabolic rate. However in rodents, caloric restriction appears to extend life span without altering metabolic rate. Well-established evidence supports beneficial effects of caloric restriction on aging and age-related diseases in several animal models, but the precise mechanisms of how or why this occurs remain unclear. It seems likely that leanness, rather than food restriction per se, may be the key element in increasing lifespan in FIRKO mice.

Although preliminary, this study has broad implications. A 30 percent food-restricted diet is extremely unlikely to become a widespread practice among the general population without the aid of a caloric restriction mimetic agent. This study presents novel and exciting findings, which suggest that the anti-aging protective effects of caloric restriction might be achievable by indirect mechanisms, eliminating the need to diet.

The paper from Kahn and coworkers is interesting and deserves greater attention. The expanded life expectancy due to leanness caused by a selective loss of insulin signalling in adipose tissue may point to an active metabolic role of that tissue. In this respect, work of other people suggests that leptin derived from adipose tissue may be involved in this process, see JF Caro et al., 1996; A Hamann et al., 1996; B Ahren et al., 1997; J Auwerx, B Staels, 1998; G Chen et al., 1996; N Barzilai et al., 1997. However, one important question remains unanswered: Is extended longevity accompanied by a stable quality of life, particularly with regard to mental health? It is tempting to asssume some relationship between Kahn's data and sporadic AD. In their textbooks published around 150 years and 100 years ago, Lorenz Geist, Emil Kraepelin, and Eugen Bleuler described the "classical" AD patient as being lean to gaunt in spite of normal to supernormal food intake. Provided that in sporadic AD, the observed disturbance in insulin signaling is not limited to neuronal tissue but also occurs in adipose tissue, a more general abnormality in insulin signaling in sporadic AD may be assumed. Studies on adipose tissue should clarify this issue.